Abstract The novel SARS-CoV-2 Coronavirus has, within a short time, caused a worldwide pandemic of epic proportions and unprecedented dimensions in modern times. As previously observed in the HIV-1 epidemic, understanding the complex pathogenesis and host response of SARS-CoV-2 infection will represent the cornerstone for developing effective treatment strategies. One particularly important aspect will be to identify subpopulations of patients with increased vulnerability to SARS-CoV-2, and to understand possible connections between SARS-CoV-2 and other viral infections. Moreover, the SARS-CoV-2 pandemic occurs in the midst of the ongoing opioid epidemic in the US, and people who use opioids are likely to have specific behavioral and immunological characteristics that may increase susceptibility to severe SARS-CoV-2 infection. In the proposed work, we will perform what we consider the first dedicated analysis of virological and immunological characteristics of SARS-CoV-2 patients with HIV-1 co-infection, and with opioid abuse. Our work will focus on identifying SARS-CoV-2/HIV-1 co-infected patients with or without opioid abuse, using large cohorts of SARS-CoV-2 patients that are currently actively enrolling in the Boston area (Specific aim 1). Using well pedigreed samples from such patient cohorts available through a centralized biorepository, we will conduct virological and immunological studies to define the replicative behavior of SARS-CoV-2 in such patients and characterize host immune cell perturbations and inflammatory markers, relative to SARS-CoV-2 -monoinefcetd patients (Specific aim 2). Finally, we will determine how SARS-CoV-2 infection affects viral reservoir cells in HIV-1 infected patients, a question of important significance as modeling predicts that a large proportion of all US citizens, and of all US-based HIV-1-patients, may ultimately be exposed and infected with SARS-CoV-2 (Specific aim 3). Together, these proposed studies will address fundamental question of SARS-CoV-2 pathogenesis and critically define the understanding of SARS-CoV-2 pathogenesis in HIV-1 patients.